Characterization of the Humoral Immune Response in Rats and Non-human Primates Exposed to Aerosolized Virulent Rift Valley Fever Virus

Rift Valley fever virus (RVFV) is an emerging zoonotic pathogen that has been responsible for extensive and devastating outbreaks of disease in both humans and livestock throughout Africa and the Arabian Peninsula. Humans infected with RVFV can recover after a brief febrile illness or go on to develop a more severe outcome including encephalitis, hepatitis, or hemorrhagic fever. Although human transmission primarily occurs through direct interaction with sick animals, inhalational infection can occur, making aerosolized RVFV a plausible bioweapon with potential for severe public health consequences. RVFV does not have a well-characterized rat or non-human primate (NHP) model for aerosol challenge. Animal models are essential for the testing of medical countermeasures, with knowledge of the host immune response aiding in their development. To further our understanding of the role that antibodies play in shaping the outcome of respiratory disease, inbred rats and non-human primates were exposed to aerosolized RVFV. Wistar-Furth, ACI, and Lewis rats were challenged in median lethal dose and serial sacrifice studies from which samples were tested to determine the robustness and timing of the IgG response. Wistar-Furth rats succumbed to hepatic disease shortly after infection, and never mounted a detectable antibody response. ACI and Lewis rats developed neurologic disease, with IgG appearing 6 d.p.i. and potentially influencing host survivability. To investigate the significance of the humoral response during respiratory infection of NHPs, cynomolgus macaques, rhesus macaques, African Green monkeys, and marmosets, were inoculated with RVFV via aerosol route, with blood samples taken at several time points. Cynomolgus and rhesus species were not sensitive to developing disease, but elicited strong IgG and neutralizing antibodies in response to inoculation. AGMs and marmosets showed moderate to high susceptibility to neurologic disease, even in the presence of extremely high titers of neutralizing antibodies. Further immunity studies are pertinent to better comprehend these host-pathogen interactions after RVFV aerosol challenge

Distinguishing pedigree relationships via multi-way identity by descent sharing and sex-specific genetic maps

The proportion of samples with one or more close relatives in a genetic dataset increases rapidly with sample size, necessitating relatedness modeling and enabling pedigree-based analyses. Despite this, relatives are generally unreported and current inference methods typically detect only the degree of relatedness of sample pairs and not pedigree relationships. We developed CREST, an accurate and fast method that identifies the pedigree relationships of close relatives. CREST utilizes identity by descent (IBD) segments shared between a pair of samples and their mutual relatives, leveraging the fact that sharing rates among these individuals differ across pedigree configurations. Furthermore, CREST exploits the profound differences in sex-specific genetic maps to classify pairs as maternally or paternally related—e.g., paternal half-siblings—using the locations of autosomal IBD segments shared between the pair. In simulated data, CREST correctly classifies 91.5%–100% of grandparent-grandchild (GP) pairs, 80.0%–97.5% of avuncular (AV) pairs, and 75.5%–98.5% of half-siblings (HS) pairs compared to PADRE’s rates of 38.5%–76.0% of GP, 60.5%–92.0% of AV, 73.0%–95.0% of HS pairs. Turning to the real 20,032 sample Generation Scotland (GS) dataset, CREST identified seven pedigrees with incorrect relationship types or maternal/paternal parent sexes, five of which we confirmed as mistakes, and two with uncertain relationships. After correcting these, CREST correctly determines relationship types for 93.5% of GP, 97.7% of AV, and 92.2% of HS pairs that have sufficient mutual relative data; the parent sex in 100% of HS and 99.6% of GP pairs; and it completes this analysis in 2.8 h including IBD detection in eight threads

Trigger Mechanism of Solar Subflares in a Braided Coronal Magnetic Structure

Fine-scale braiding of coronal magnetic loops by continuous footpoint motions may power coronal heating via nanoflares, which are spontaneous fine-scale bursts of internal reconnection. An initial nanoflare may trigger an avalanche of reconnection of the braids, making a microflare or larger subflare. In contrast to this internal triggering of subflares, we observe external triggering of subflares in a braided coronal magnetic field observed by the {\it High-resolution Coronal Imager (Hi-C)}. We track the development of these subflares using 12 s cadence images acquired by {\it SDO}/AIA in 1600, 193, 94 \AA, and registered magnetograms of {\it SDO}/HMI, over four hours centered on the {\it Hi-C} observing time. These data show numerous recurring small-scale brightenings in transition-region emission happening on polarity inversion lines where flux cancellation is occurring. We present in detail an example of an apparent burst of reconnection of two loops in the transition region under the braided coronal field, appropriate for releasing a short reconnected loop downward and a longer reconnected loop upward. The short loop presumably submerges into the photosphere, participating in observed flux cancellation. A subflare in the overlying braided magnetic field is apparently triggered by the disturbance of the braided field by the reconnection-released upward loop. At least 10 subflares observed in this braided structure appear to be triggered this way. How common this external trigger mechanism for coronal subflares is in other active regions, and how important it is for coronal heating in general, remain to be seen.Comment: 6 pages, 4 figures, 1 table; ApJ Letters, in pres

Belimumab : a technological advance for systemic lupus erythematosus patients? Report of a systematic review and meta-analysis

Objectives: To undertake a systematic review and meta-analysis to investigate clinical effectiveness of belimumab for patients with systemic lupus erythematosus (SLE) and antinuclear and/or anti-double-stranded DNA (dsDNA) autoantibodies. Methods: We searched eight electronic databases and reference lists for randomised controlled trials (RCTs) of belimumab against placebo or best supportive care. Quality assessment and random effects meta-analysis were undertaken. Design: A meta-analysis of RCTs. Participants: 2133 SLE patients. Primary and secondary outcome measures: SLE Responder Index (SRI) at week 52. Results: Three double-blind placebo-controlled RCTs (L02, BLISS-52 BLISS-76) investigated 2133 SLE patients. BLISS-52 and BLISS-76 trials recruited patients with antinuclear and/or anti-dsDNA autoantibodies and demonstrated belimumab effectiveness for the SRI at week 52. Ethnicity and geographical location of participants varied considerably between BLISS trials. Although tests for statistical heterogeneity were negative, BLISS-52 results were systematically more favourable for all measured outcomes. Meta-analysis of pooled 52-week SRI BLISS results showed benefit for belimumab (OR 1.63, 95% CI 1.27 to 2.09). By week 76, the primary SRI outcome in BLISS-76 was not statistically significant (OR 1.31, 95% CI 0.919 to 1.855)

What can we learn about immediate memory from the development of children's free recall?

We ask the question: Which aspects of immediate memory performance improve with age? In two studies, we reexamine the widely held view that primary memory capacity estimates derived from children's immediate free recall are age invariant. This was done by assessing children's immediate free-recall accuracy while also measuring the order in which they elected to recall items (Experiment 1) and by encouraging children to begin free recall with items from towards the end of the presented list (Experiment 2). Across samples aged between 5 and 8 years we replicated the previously reported age-related changes in free-recall serial position functions when aggregated across all trials of the standard task, including an absence of age differences in the recency portion of this curve. However, we also show that this does not reflect the fact that primary memory capacity is constant across age. Instead, when we incorporate order of report information, clear age differences are evident in the recall of list-final items that are output at the start of a participant's response. In addition, the total amount that individuals recalled varied little across different types of free-recall tasks. These findings have clear implications for the use of immediate free recall as a means of providing potential indices of primary memory capacity and in the study of the development of immediate memory

Early maternal death following child removal:—A short report using observational data

Key Practitioner Messages• Mothers who have a child removed from their care often face a range of vulnerabilities, such as abuse in childhood, isolation, poverty, poor mental health, domestic abuse, and substance misuse, which contribute to the reasons for their children being removed.• Yet following this removal, and at a time of acute need for them due to the trauma involved, birth mothers frequently disappear from the gaze of services, as children's services are structured to meet the needs of the child.• There is evidence that mothers who have a child removed are at a significantly increased risk of early death.• While the need for support for the children is irrefutable, equally there needs to be specialist support for their mothers, which goes beyond children's services and involves health services

Combining Experimental Evolution and Genomics to Understand How Seed Beetles Adapt to a Marginal Host Plant

Genes that affect adaptive traits have been identified, but our knowledge of the genetic basis of adaptation in a more general sense (across multiple traits) remains limited. We combined population-genomic analyses of evolve-and-resequence experiments, genome-wide association mapping of performance traits, and analyses of gene expression to fill this knowledge gap and shed light on the genomics of adaptation to a marginal host (lentil) by the seed beetle Callosobruchus maculatus. Using population-genomic approaches, we detected modest parallelism in allele frequency change across replicate lines during adaptation to lentil. Mapping populations derived from each lentil-adapted line revealed a polygenic basis for two host-specific performance traits (weight and development time), which had low to modest heritabilities. We found less evidence of parallelism in genotype-phenotype associations across these lines than in allele frequency changes during the experiments. Differential gene expression caused by differences in recent evolutionary history exceeded that caused by immediate rearing host. Together, the three genomic datasets suggest that genes affecting traits other than weight and development time are likely to be the main causes of parallel evolution and that detoxification genes (especially cytochrome P450s and beta-glucosidase) could be especially important for colonization of lentil by C. maculatus

The effect of body mass index on smoking behaviour and nicotine metabolism : a Mendelian randomization study

Given clear evidence that smoking lowers weight, it is possible that individuals with higher body mass index (BMI) smoke in order to lose or maintain their weight. We performed Mendelian randomization (MR) analyses of the effects of BMI on smoking behaviour in UK Biobank and the Tobacco and Genetics Consortium genome-wide association study (GWAS), on cotinine levels and nicotine metabolite ratio (NMR) in published GWAS and on DNA methylation in the Avon Longitudinal Study of Parents and Children. Our results indicate that higher BMI causally influences lifetime smoking, smoking initiation, smoking heaviness and also DNA methylation at the aryl-hydrocarbon receptor repressor (AHRR) locus, but we do not see evidence for an effect on smoking cessation. While there is no strong evidence that BMI causally influences cotinine levels, suggestive evidence for a negative causal influence on NMR may explain this. There is a causal effect of BMI on smoking, but the relationship is likely to be complex due to opposing effects on behaviour and metabolism.Peer reviewe

Patterns of predation and meat-eating by chacma baboons in an Afromontane environment

Meat-eating among non-human primates has been well documented but its prevalence among Afromontane baboons is understudied. In this study we report the predatory and meat-eating behaviours of a habituated group of gray-footed chacma baboons (Papio ursinus griseipes) living in an Afromontane environment in South Africa. We calculated a vertebrate-eating rate of 1 every 78.5 hours, increasing to 58.1 hours when unsuccessful predation attempts were included. A key food source was young antelopes, particularly bushbuck (Tragelaphus scriptus), which were consumed once every 115 observation hours. Similar to other baboon research sites, predations seemed mostly opportunistic, adult males regularly scrounged and monopolised prey, there was no evidence they used an active kill bite, and active sharing was absent. This is the first baboon study to report predation of rock python (Python sebae) eggs and likely scavenging of a leopard (Panthera pardus) kill (bushbuck) cached in a tree. We also describe several scramble kleptoparasitism events, tolerating active defence from antelope parents, and the baboons inhibiting public information about predations. In the latter case, baboons with meat often hid beyond the periphery of the group, reducing the likelihood of scrounging by competitors. This often led to prey carcasses being discarded without being fully exploited and potentially providing resources to scavengers. We also highlight the absence of encounters with numerous species, suggesting the baboons are a key component of several species’ landscapes of fear. Given these findings it seems likely that their ecological role in the Soutpansberg has been undervalued, and such conclusions may also hold for other baboon populations